Calorie restriction mimetics – focus on avocado extract

I have written about calorie restriction (CR) a number of times in this blog. CR is the most-proven approach to life extension, involving an ancient biological pathway that works across a variety of species. This blog entry focuses on CR mimetics, substances that can presumably produce the same results as CR, and focuses particularly on mannoheptulose, a sugar in avocados that seems to do the trick.

Actually, a number of substances have been proposed as CR mimetics including several in the anti-aging firewalls combined supplement regimen: resveratrol, carnosine, alpha-lipoic acid, acetyl-l-carnitine, and mixed antioxidants(ref).The proposed list also includes metformin, gymnema, 2-deoxyglucose, aminoguanidine, hydroxycitrate, thiazolidinediones, lodoacetate, modulators of NPY, exandin, PYY3-36, leptin, oxaloacetate, cinnamon and avocado extract.I focus here on avocado extract because there seems to be some solid research relating to it.

A 2009 publication from researchers at several collaborating institutions tells the story, Mannoheptulose: glycolytic inhibitor and novel caloric restriction mimetic. “Caloric restriction (CR) is the most robust and reproduciblestrategy for retarding aging. Benefits of CR have been demonstratedin multiple species, but application to human or companion animalaging represents a challenge. In 1998 the concept of CR “mimetic”(CRM) was introduced as a method to obtain “anti-aging” andhealth-promoting benefits of CR without reducing food intake.We hypothesized that an effective CRM would best mimic the effectsof CR if it impeded initial stages of energy metabolism. Wefocused initially on glycolytic inhibition using 2-deoxyglucose(2DG). Upon entry into cells, this glucose analog is phosphorylatedand becomes a strong competitive inhibitor of phosphohexoseisomerase. 2DG effectively induces a CR-like state in ratsbased on metabolic effects such as reduced plasma glucose, insulin,body temperature, pulse, heart rate and inhibiting tumor growth.Results show 2DG has a narrow window between efficacy and toxicityso recently we shifted our focus to mannoheptulose (MH), a seven-carbonsugar that reduces glycolysis via hexokinase inhibition. MHappears non-toxic with negligible effects on food intake andBW, and increased insulin tolerance by 25% in mice. MH extendsmedian and maximal lifespan (~15%) in D. melanogaster and medianlifespan (~30%) in C3H/HeJ mice. These findings, coupled withsimple extraction from avocados, suggest that MH may be a practical,highly effective CRM.”

“Mannoheptulose is a hexokinase inhibitor. It is a heptose, a monosaccharide with seven carbon atoms. By blocking the enzyme hexokinase, it prevents glucose phosphorylation. As a result less dextrose units are broken down into smaller molecules in an organism. It is found as D-mannoheptulose in avocado(ref).[1]” In simple terms, it works to block the metabolism if glucose.

From ScienceNews April 20, 2009“So Roth and his team (from P&G Pet Care, Wayne State University, Southern Illinois University and the Pennington Biomedical Research Institute) have been mining avocados for an alternative — MH (for mannoheptulose). It’s a fairly simple sugar with a 7-carbon backbone. — When fed to mice in fairly concentrated doses (roughly 300 milligrams per kilogram of an animal’s body weight), it improved insulin sensitivity and the clearance of glucose from the blood. Meaning it helped overcome diabetes-like impairments to blood-sugar control. MH supplementation also improved the ability of insulin, a hormone, to get cells throughout the body to do its bidding (and that’s a good thing). –MH revved up the burning of fats in muscle. That’s the opposite of fat deposition and something that these scientists note “would be an expected effect of a calorie restriction mimetic.”— Treated mice also lived longer — some 30 percent longer than untreated animals. And they were happier, I’m guessing, because they didn’t have to give up most of their chow to achieve this life extension. Indeed, their food intake and weight matched that of untreated mice.”

I remark that the 30% life extension in normal mice from taking mannoheptulose beats the 0% life extension in normal mice achievable from taking resveratrol.Resveratrol appears to extend the lives only of obese mice on a high-calorie diet, extending their lifespans to those of normal mice(ref).

I note that the supplement industry is already out-there marketing avocado extract with write-ups describing weight loss, control of hypoglycemia, promotion of heart-health and other benefits(ref).For example, see this avocado extract “obesity protocol.”It appears that the available supplements include at least one product with standardized mannoheptulose sugar content(ref).

I mention again that I have no affiliation with or economic interest in any providers of foods, medicines or health supplements or products.But I do love avocados and eat them at every opportunity.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at www.vincegiuliano.com and an extensive site of my art at www.giulianoart.com.
Please note that I have recently changed my mailbox to vegiuliano@agingsciences.com.

Throughout history mankind has had a burning desire to find ways to add to the length of their lifespan.

There are many foods and activities that have been shown to maximize the length of ones life depending upon the inherent genetic composition of ones heritage.

The telomere theory of life span indicates every time a cell dies and a new cell splits, the length of the telomere is shortened. Once the cell has become too short, the cell no longer can divide into two new cells. Human growth hormone has been shown to have the capability of elongating the telomere and as such, if the theory is correct, is a basic ingredient in adding to oneâ€™s lifespan. For more of a history on HGH come to our website at Stop Age.

Sorry, I disagree. First of all, despite many years of hope, there is no evidence that telomere-elongation increases human lifespan though it may have other positive health effects. I have researched and written very extensively about this as you can see by searching in this blog or checking out my treatise at http://www.vincegiuliano.name/Antiagingfirewalls.htm. Show me one experiment where telomere elongation has extended the lives of normal mice or other mammals. I can show you hundreds of papers where other interventions have extended such lives.

I suggest that the place to look for valid information is in the aresponsible research literature and that statements in commercial sites that sell anti-aging supplements or services need to be checked out carefully.
Vince

Thoughts on C3H8O3
Glucose-To-Glycerol Conversion In Long-lived Yeast Provides Anti-aging Effects
ScienceDaily (May 13, 2009) â€” Cell biologists have found a more filling substitute for caloric restriction in extending the life span of simple organisms.

In a study published May 8 in the open-access journal PLoS Genetics, researchers from the University of Southern California Andrus Gerontology Center show that yeast cells maintained on a glycerol diet live twice as long as normal — as long as yeast cells on a severe caloric-restriction diet. They are also more resistant to cell damage.

Many studies have shown that caloric restriction can extend the life span of a variety of laboratory animals. Caloric restriction is also known to cause major improvements in a number of markers for cardiovascular diseases in humans. This study is the first to propose that “dietary substitution” can replace “dietary restriction” in a living species.

“If you add glycerol, or restrict caloric intake, you obtain the same effect,” said senior author Valter Longo. “It’s as good as calorie restriction, yet cells can take it up and utilize it to generate energy or for the synthesis of cellular components.”

Longo and colleagues Min Wei and Paola Fabrizio introduced a glycerol diet after discovering that genetically engineered long-lived yeast cells that survive up to 5-fold longer than normal have increased levels of the genes that produce glycerol. In fact, they convert virtually all the glucose and ethanol into glycerol. Notably, these cells have a reduced activity in the TOR1/SCH9 pathway, which is also believed to extend life span in organisms ranging from worms to mice.

When the researchers blocked the genes that produce glycerol, the cells lost most of their life span advantage. However, Longo and colleagues believe that the “glucose to glycerol” switch represents only a component of the protective systems required for the extended survival. The current study indicates that glycerol biosynthesis is an important process in the metabolic switch that allows this simple organism to activate its protective systems and live longer.

“This is a fundamental observation in a very simple system,” Longo said, “that at least introduces the possibility that you don’t have to be calorie-restricted to achieve some of the remarkable protective effects of the hypocaloric diet observed in many organisms, including humans. It may be sufficient to substitute the carbon source and possibly other macronutrients with nutrients that do not promote the “pro-aging” changes induced by sugars.”

Funding for the study came from the American Federation for Aging Research and the National Institute on Aging (NIH).